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Hawthorn, a well-known traditional Chinese medicine is used for the treatment of dyspepsia syndrome, cardiovascular disease, and hyperlipidemia. Hawthorn has complex composition. However, the effective fraction and mechanisms of action in alleviating hyperlipidemia are unknown. Therefore, the aim of this study was to evaluate the effects of four different polar components of hawthorn on hyperlipidemia rats, and to explore underlying mechanisms of action through liquid chromatography-mass spectrometry based plasma metabolomics. Hyperlipidemia rat model was established by feeding rats using a high-fat diet. High-fat model rats were then treated with four polar components of hawthorn for 14 consecutive days. Plasma samples were collected and subjected to biochemical and metabolomics analysis. Biochemical analysis showed that hawthorn n-butanol and ethyl acetate extracts had the highest efficacy on hyperlipidemia rats. Water fraction showed a partial effect, whereas petroleum ether extract was not effective against hyperlipidemia rats. Furthermore, liquid chromatography-mass spectrometry metabolomics analysis showed that the most effective fraction of hawthorn reversed the metabolic disorder in plasma of hyperlipidemia rats. Metabolomics analysis showed that hawthorn exerts its activity by modulating lipid metabolism, energy metabolism, oxidative stress, and amino acid metabolism., (© 2021 Wiley-VCH GmbH.)

Traditional Chinese medicines (TCMs) have been widely used in Asian countries for thousands of years due to their supreme quality and good clinical efficacy. However, the increasing demand for TCMs in recent decades warrants effective quality control methodology to avoid clinical problems. Therefore, comprehensive quality evaluation systems should be established for ensuring TCM's quality, in terms of chemical components, as well as bioactivity for identifying quality markers in TCM and developing suitable analytical methods for quality control. In this study, we selected Sophora flavescens (S. flavescens) as the research object and developed a novel integrated strategy combining metabolomics and network pharmacology to explore the quality markers. Firstly, we determined the targeted metabolomic profiles of seventy-four batches of S. flavescens (aged from 1 to 6 years) by UHPLC/QE-MS. Six potential markers were successfully screened, quantified and reverse-verified as the most influential effective compounds by UHPLC/QE-MS and multivariate statistical analysis. Secondly, the network of "components-targets-pathways" was constructed, and the pharmacological activities of six potential markers were predicted. Finally, we determined the anti-tumor activity of six flavonoids (kurarinone, norkurarinone, kuraridin, kushenol N, trifolirhizin, and genistein) as the quality markers for Sophora flavescens, evaluated their pharmacokinetic profiles and reviewed their existing pharmacological researches. Thus, integrated metabolomics and network pharmacology technology were applied for the effective discovery of quality markers of Chinese material medica., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Naodesheng (NDS) is a widely used traditional Chinese medicine (TCM) prescription for the treatment of ischemic stroke. A combination of 10 components is derived from NDS. They are: Notoginsenoside R1, ginsenoside Rg1, ginsenoside b1, ginsenoside Rd, hydroxysafflor yellow A, senkyunolide I, puerarin, daidzein, vitexin, and ferulic acid. This study aimed to investigate the protective effect of the ten-component combination derived from NDS (TCNDS) on ischemic stroke rats with a middle cerebral artery occlusion (MCAO) model by integrating an NMR-based metabonomics approach with biochemical assessment. Our results showed that TCNDS could improve neurobehavioral function, decrease the cerebral infarct area, and ameliorate pathological features in MCAO model rats. In addition, TCNDS was found to decrease plasma lactate dehydrogenase (LDH) and malondialdehyde (MDA) production and increase plasma superoxide dismutase (SOD) production. Furthermore, 1 H-NMR metabonomic analysis indicated that TCNDS could regulate the disturbed metabolites in the plasma, urine, and brain tissue of MCAO rats, and the possible mechanisms were involved oxidative stress, energy metabolism, lipid metabolism, amino acid metabolism, and inflammation. Correlation analysis were then performed to further confirm the metabolites involved in oxidative stress. Correlation analysis showed that six plasma metabolites had high correlations with plasma LDH, MDA, and SOD. This study provides evidence that an NMR-based metabonomics approach integrated with biochemical assessment can help to better understand the underlying mechanisms as well as the holistic effect of multiple compounds from TCM.

Chronic cold stress can trigger biochemical and physiological changes in living organisms, which leads to a rapid loss of homeostasis. However, the biochemical responses of the organism to chronic cold stress are unclear. In this study, we systematically analysed the metabonomic changes under chronic cold stress by using a (1)H NMR-based metabonomics approach in conjunction with clinical biochemistry assessments. We found that chronic cold exposure caused significant elevation in the levels of lipoproteins (HDL, LDL), lactate, acetoacetate, creatine, creatinine, choline metabolites (GPC, PC and betaine), TMAO and taurine but reduction in the levels of VLDL, glutamine, glycine and glycerol in plasma. Increased levels in urinary TCA cycle intermediates (2-ocoglutarate and citrate), acetoacetate, taurine, TMAO, betaine and hippurate were also found in model rats, together with the reduction of creatinine and tryptophan levels. The results indicated that chronic cold stress caused widespread metabolic changes involved in lipid and energy metabolism, gluconeogenesis, the TCA cycle, and gut microbiota disorders, accompanied with hepatic and renal dysfunction. These findings provide a comprehensive insight into the biochemical consequences and metabolic responses to chronic cold stress in rats.

Diets rich in high fructose and salt are increasingly popular in our daily life. A combination consumption of excessive fructose and salt can induce insulin resistance (IR) and hypertension (HT), which are major public health problems around the world. However, the effects of high fructose and salt on systematic metabonome remain unknown, which is very important for revealing the molecular mechanism of IR and HT induced by this dietary pattern. The metabolic profiling in urine, plasma, and fecal extracts from high fructose and salt-fed rats was investigated by use of (1) H nuclear magnetic resonance (NMR)-based metabonomics approach in this study. Multivariate analysis of NMR data showed the effects of high fructose and salt on the global metabonome. The metabolite analysis in urine and fecal extracts showed the time-dependent metabolic changes, which displayed metabonomic progression axes from normal to IR and HT status. The changes of 2-oxoglutarate, creatine and creatinine, citrate, hippurate, trimethylamine N-oxide (TMAO), and betaine in urine, together with gut microbiota disorder in feces, were observed at the preliminary formation stage of IR and HT (fourth week). At the severe stage (eighth week), the previously mentioned metabolic changes were aggravated, and the changes of lipid and choline metabolism in plasma suggested the increased risk of cardiovascular diseases. These findings provide an overview of biochemistry consequences of high fructose and salt feeding and comprehensive insights into the progression of systematic metabonome for IR and HT induced by this dietary pattern., (Copyright © 2015 John Wiley & Sons, Ltd.)

Insulin resistance (IR) is a common risk factor for the development of metabolic diseases, and has gradually become a hot issue for research. It was reported that excessive feeding with high fructose induced insulin resistance in both humans and rats. The aim of this study was to investigate the progression of IR and identify potential biomarkers in urine, plasma and fecal extracts of high fructose-fed rats using a (1)H NMR-based metabonomics approach. The biochemical analysis was also performed. The levels of pyruvate and lactate in the plasma of the IR model rats were reduced significantly, and the levels of citrate and α-ketoglutaric acid (α-KG) in their urine, and the levels of succinate in their feces also decreased, suggesting perturbation of energy metabolism. Decreased levels of taurine in urine and fecal extracts during the whole experiment, together with increased levels of creatine/creatinine in urine, revealed liver and kidney injuries. Decreased levels of choline-containing metabolites in urine and increased levels of betaine in urine and plasma demonstrated altered transmethylation. Changes in hippurate, acetate, propionate and n-butyrate levels suggested disturbance of the intestinal flora in the IR rats. This study indicated that (1)H NMR-based metabonomics can provide biochemical information on the progression of IR and offers a non-invasive means for the discovery of potential biomarkers.

Esophageal carcinoma (EC) is one of the most common malignant tumors. EC survival has remained disappointingly low because of the high malignancy of esophageal cancer and the lack of obvious clinical symptoms at an early stage. Early diagnosis is often difficult because the small tumor nodules are frequently missed. Metabonomics based on high-resolution magic-angle spinning (HRMAS) NMR has been popular for tumor detection because it is highly sensitive, provides rich biochemical information and requires no sample pretreatment. (1)H HRMAS spectra of non-involved adjacent esophageal tissues and of well differentiated and moderately differentiated esophageal carcinoma tumors were recorded and analyzed by use of multivariate and statistical analysis techniques. Moderately differentiated EC tumors were found to have increased total choline, alanine, and glutamate and reduced creatine, myo-inositol, and taurine compared with non-involved adjacent tissues. Moreover, clear differences between the metabonomic profiles of EC tissues enabled tumor differentiation. Furthermore, the integral Gly/MI ratio for samples of different tissue types were statistically significantly different; this was sufficient both for distinguishing non-involved tissues from esophageal carcinoma and for classification of well differentiated and moderately differentiated EC tumors.

Objective: To investigate the metabolic profile of hydrocortisone-induced 'Kidney-yang deficiency syndrome'in rats and the intervention effects of Morinda officinalis., Method: Proton nuclear magnetic resonance (1H-NMR) technique was used to analyze the rat metabonome in serum. Orthogonal partial least squares discriminant analysis (OPLS-DA) were processed to analyze the metabonome difference between the control and hydrocortisone treated samples. Twelve potential biomarkers were selected, via the parameter of variable importance in the projection (VIP). Principal components analysis (PCA) was employed to process the data from the M. officinalis. treatment group and the intervention effects of M. officinalis, was investigated through the selected potential biomarkers., Result: After hydrocortisone treatment, the energy metabolism, amino acids metabolism and gut microflora environment were seriously disturbed and transmethylation was surpressed. M. officinalis could effectively alleviate the disturbance of energy and amino acids metabolism and enhance transmethylation, but could not modulate the gut microflora environment., Conclusion: The results obtained suggested that metabonomic studies could better reflect the whole status of metabolism in bio-systems, and could be treated as a potential powerful approach in pharmacological studies and investigation of the essence of 'syndrome' in traditional Chinese medicine.

Porcine models are increasingly recognized for their similarities to humans and have been utilized in disease modeling and organ grafting research. While extensive metabolomics studies have been conducted in swine, primarily focusing on conventional cohorts or specific animal models, the composition and functions of fecal metabolites in pigs across different age groups—particularly in the elderly—remain inadequately understood. In this study, an untargeted metabolomics approach was employed to analyze the fecal metabolomes of pigs at three distinct age stages: young (one year), middle-aged (four years), and elderly (eight years). The objective was to elucidate age-associated changes in metabolite composition and functionality under standardized rearing conditions. The untargeted metabolomic analysis revealed a diverse array of age-related metabolites. Notably, L-methionine sulfoxide levels were found to increase with age, whereas cytidine-5-monophosphate levels exhibited a gradual decline throughout the aging process. These metabolites demonstrated alterations across various biological pathways, including energy metabolism, pyrimidine metabolism, lipid metabolism, and amino acid metabolism. Collectively, the identified key metabolites, such as L-methionine sulfoxide and Cholecalciferol, may serve as potential biomarkers of senescence, providing valuable insights into the mechanistic understanding of aging in pigs. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS), as a leading cause of disability worldwide, affects intestinal bacterial communities and their metabolites, while recent discoveries have highlighted the importance of the intestinal microflora in the development of IS. Systematic investigations of complex intestinal bacterial communities and their metabolites during ischemic brain injury contribute to elucidate the promising therapeutic targets for IS. However, the associations between intestinal microbiota and related circulating metabolic processes in IS remained unclear. Hence, to identify the changed microflora and their metabolites in IS of NaoMaiTong (NMT), an effective clinical medication, we established the middle cerebral artery occlusion/reperfusion (MCAO/R) model using conventionalized and pseudo-germ-free (PGF) rats. Subsequently, we systematically screen the microflora and related metabolites changing in IS via an integrated approach of cecal 16S rRNA sequencing combined with plasma metabolomics. We found that NMT relied on intestinal flora to improve stroke outcome in conventionalized rats while the protection of NMT was reduced in PGF rats. Total 35 differential bacterial genera and 26 differential microbial metabolites were regulated by NMT. Furthermore, L-asparagine and indoleacetaldehyde were significantly negatively correlated with Lachnospiraceae_UCG.001 and significantly positively correlated with Lachnoclostridium. Indoleacetaldehyde also presented a negative correlation with Lactobacillus and Bifidobacterium. 2-Hydroxybutyric acid was strongly negatively correlated with Ruminococcus, Lachnospiraceae_UCG.001 and Lachnospiraceae_UCG.006. Creatinine was strongly negatively correlated with Akkermansia. In summary, the research provided insights into the intricate interaction between intestinal microbiota and metabolism of NMT in IS. We identified above differential bacteria and differential endogenous metabolites which could be as prebiotic and probiotic substances that can influence prognosis in stroke and have potential to be used as novel therapeutic targets or exogenous drug supplements. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is considered an immune disease, which is related to the dysbiosis of intestinal microbiota and disorders of the host immune system and metabolism. Sophora flavescens Aiton has been used for the clinical treatment of UC in China and East Asia for thousands of years. It has many traditional prescriptions and modern preparations, and its curative effects are definite. We are the first to report that the flavonoids in Sophora flavescens (S. flavescens) Aiton EtOAc extract (SFE) could potentially attenuate the dextran sodium sulfate–induced UC in mice, which changed the current understanding of considering alkaloids as the only anti-UC pharmacological substances of S. flavescens Aiton. Based on the 16S rRNA gene sequencing and metabolomic analysis, it was found that the anti-UC effects of SFE were due to the regulation of gut microbiota, reversing the abnormal metabolisms, and regulation of the short-chain fatty acids synthesis. Notably, according to the interaction networks of specific bacteria and "bacteria and metabolites" co-expression network, the SFE could enrich the abundance of the commensal bacterium Lactobacillus , Roseburia , norank_f__Muribaculaceae , Anaerotruncus , Candidatus_Saccharimona , and Parasutterella , which are proposed as potentially beneficial bacteria, thereby playing vital roles in the treatment of UC. [ABSTRACT FROM AUTHOR]

Dyspepsia, one of the most prevalent diseases of the digestive tract that impacts the quality of patient life, is mainly caused by gastrointestinal motility disorder. Hawthorn is a commonly used traditional Chinese medicine for treating dyspepsia, and has been proven to improve gastrointestinal motility. Herein, a rat model of gastrointestinal motility disorder was established by subcutaneous injection with atropine. The modeled rats were treated with four polar parts (T1–4 in descending polarity, corresponding to water, n‐butanol, ethyl acetate and petroleum ether extracts, respectively) of hawthorn. Through metabolomics analysis, a total of 20 significantly metabolites were identified with significant changes in their abundance levels and these metabolites were related to many metabolic pathways such as amino acid metabolism and primary bile acid biosynthesis. The results showed that T3 had the best therapeutic effect of promoting gastrointestinal motility. Other parts showed no obvious therapeutic effect, demonstrating that the effective components of hawthorn may be compounds of medium polarity. T3 might achieve good therapeutic effects owing to the gastrointestinal motility promotion activity, and by rectifying the disturbed metabolic pathways in the gastrointestinal motility disorder model. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) has attracted worldwide attention due to the high mortality and disability rate. Raw rhubarb (RR) is a traditional medicinal plant and whole-food that has been used in China for its various pharmacological activities, such as antioxidant and anti-inflammatory properties. Recent pharmacological research has shown the role of RR against IS, but its mechanism of action remains unclear, particularly in the context of the brain-gut axis. To address this gap in knowledge, the present study was conducted in the middle cerebral artery occlusion/reperfusion (MCAO/R) model with the aim of investigating the effects of RR on regulating the intestinal microbiota barrier and metabolism and thereby reducing inflammatory response so as to improve the IS. The results showed that pre-treatment of RR attenuated cerebral infarct area and inflammation response in MCAO rats. Furthermore, RR also improved intestinal barrier function, including the integrity and permeability of the intestinal barrier. Additionally, RR intervention significantly attenuated gut microbiota dysbiosis caused by ischemic stroke, especially the increased Firmicutes. Notably, the pseudo-germ-free (PGF) rats further demonstrated that the anti-stroke effect of RR might rely on intestinal microbiota. In addition, the UPLC/Q-Orbitrap-MS-Based metabolomics revealed the disrupted metabolic profiles caused by MCAO/R, and a total of 11 differential metabolites were modulated by RR administration, especially bile acids. Further correlation analysis and network pharmacology analysis also demonstrated a strong association between specific bacteria, such as Firmicutes and bile acids. In conclusion, our work demonstrated that RR could effectively ameliorate ischemic stroke by modulating the microbiota and metabolic disorders. The protective effect and the potential mechanism of raw rhubarb in the occurrence of ischemic stroke by the regulation of intestinal microbiota and metabolism [Display omitted] • Raw rhubarb effectively alleviates the disorder of intestinal microbiota and metabolism in ischemic stroke. • The effect of raw rhubarb against ischemic stroke relies on the presence of intestinal flora. • The Firmicutes and bile acids metabolites may be the targets for RR in ischemic stroke. [ABSTRACT FROM AUTHOR]

Acupuncture is an effective therapy for ischemic stroke, which has been widely used in China and gradually accepted in more countries and regions recently. In addition, Chinese medicine also plays an important role in stroke treatment, among which NaoMaiTong (NMT) is an example of an effective herbal formula for the treatment of stroke. A therapeutic strategy that combines acupuncture and medicine was widely used in stroke patients. However, the synergistic influences and mechanisms of combined acupuncture and medicine on ischemic stroke have not yet been entirely elucidated. The purpose of this study is to explore whether acupuncture and medicine combination treatments can produce synergism by using NMT, a clinically effective Chinese medicinal formula for the treatment of ischemic stroke for decades and has been demonstrated to be effective against ischemic brain injury, as a probe. Meanwhile, the potential mechanisms were investigated via cecal microbiome and plasma metabolomics to provide more strategies and basis for acupuncture-medicine combination for stroke. Adopted middle-cerebral artery occlusion/reperfusion (MCAO/R) rat models, the effect for the stroke of the combination treatment consisting of acupuncture and NMT was evaluated by detecting neurological issues, cerebral infarct dimensions, levels of inflammatory factors (IL-6, IL-1β, TNF-α) and oxidative stress factors (SOD, MDA) and brain-derived neurotrophic factor (BDNF). Subsequently,16S rRNA gene sequencing and LC/MS-based metabolomic analysis were utilized to explore the characteristics of cecal-contents microecology and plasma metabolic profile, respectively. Finally, the correlation between intestinal microecological characteristics and plasma metabolic characteristics was analyzed to explore the potential mechanism of the acupuncture-NMT combination. The efficacy of acupuncture-NMT therapy was more effective than a single treatment on ischemic stroke, with more effectively reduced infarct sizes, improved neurobehavioral deficits, and alleviated oxidative stress and inflammatory responses. Besides, the combination therapy not only adjusted gut microbiota disturbances by enriching species diversity, reducing the abundance of pathogenic bacteria (such as Escherichia-Shaigella), as well as increasing the abundance of beneficial bacteria (such as Turicibacter , Bifidobacterium), but also improved metabolic disorders by reversing metabolite plasma levels to normality. The results of the correlation analysis demonstrated a significant association between intestinal microbiota and plasma metabolic profile, especially the strong correlation of Turicibacter and isoflavones phyto-estrogens metabolites. The combination of acupuncture and NMT could produce synergism, suggesting acupuncture-medicine combination therapy might be more conducive to the recovery of ischemic stroke. And the potential mechanism was probably related to the mediation of intestinal microecology and plasma metabolism. Turicibacter and isoflavones phyto-estrogens metabolites might be the targets for acupuncture-NMT combination for stroke. Our current findings could provide a potential therapeutic strategy against ischemic stroke. [Display omitted] [ABSTRACT FROM AUTHOR]

Ischemic/reperfusion (IR) can cause adverse reactions including apoptosis, oxidative stress, and inflammation, but the existing therapeutic strategies have been limited. Moreover, the regulation of microglia plays an important role in brain injury after reperfusion. Hence, it is imperative to find new and effective drugs for modulating microglia to treat IR brain injury. Cyclic peptide compound cyclo-(Phe-Tyr) (Sparganin C, SC) is a compound isolated from Sparganii Rhizoma. However, the protective effects of SC on the central nervous system are rather unclear. In an attempt to elucidate the protective effects and mechanism of SC on cerebral damage induced by the IR, we used a middle cerebral artery occlusion reperfusion (MCAO/R) model in rats and discovered that SC significantly decreased the size of cerebral infarcts, improved neurological scores, and blocked inflammatory and oxidative factor release. Using RNA-Seq and metabolomics association analyses, SC was shown to have a protective impact through the JUNB and SOX5-related pathways. Metabolomic analysis revealed twenty-eight differentially expressed biomarkers. In addition, the detection of SC content in brain tissue using LC/MS revealed that SC had blood-brain barrier penetration. To investigate the mechanism, we established an in vitro BV2 cell oxygen-glucose deprivation/reperfusion (OGD/R) model and used siRNA as well as an inhibitor. The protective effects of SC were dependent on the JUNB and SOX5 to inhibit inflammation and apoptosis in microglia. Our findings revealed for the first that SC against IR injury by reducing inflammation and apoptosis while simultaneously acting as potential therapeutic lead compound for ischemic stroke. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • To evaluate the pharmacodynamic effects of SFE against streptozotocin-induced DR rats from multiple levels for the first time. • To study the distribution of flavonoids of Sophora flavescens Aiton in rat's aqueous humor and retina by UHPLC-MS. • To explore the mechanism of SFE against on DR based on untargeted retinal metabolomics. • To elucidate the effects, material basis and treatment mechanism of SFE on DR systematically. Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and a leading cause of vision impairment and blindness, which lacks effective diagnostic measures and therapeutic options. Sophora flavescens Aiton or "Kushen" is a traditional Chinese medicine used since ancient times, either alone or in combination, to clear heat, dampness, and tearing, and to treat ocular diseases and improve eyesight. Additionally, the flavonoids of Sophora flavescens Aiton extracted using ethyl acetate (EtOAc) (SFE) is effective in managing diabetes and diabetic vascular complications. In this study, we explored the pharmacodynamic effects and material basis of action of SFE on DR for the first time and elucidated the mechanism based on untargeted retinal metabolomics. Results from the pharmacodynamic studies showed that SFE could reduce blood glucose levels in rats, regulate serum lipopolysaccharide, tauroursodeoxycholic acid, and trimethylamine oxide levels, and significantly improve the structure of retina in rats with DR. Moreover, SFE could protect the blood-retinal barrier, reduce angiogenesis and capillary formation, and inhibit retinal nerve cell apoptosis. A total of 13 compounds were identified in the aqueous humor and retina, which were dihydroflavonoid, isoflavonoid, pterostane flavonoid, chalcone, and dihydroflavonol derivatives. In addition, 39 differential metabolites were screened based on retinal metabolomics data and 23 were found to be affected by SFE, indicating its anti-DR effect by regulating the synthetic metabolic pathways, including lactose, bile acid, glycerophospholipid, arginine, purine, and pyrimidine metabolism pathways. Collectively, our findings elucidated the effects, material basis, and treatment mechanism of SFE on DR systematically and could lay the foundation for promoting the clinical application of Sophora flavescens Aiton. [ABSTRACT FROM AUTHOR]